2-Alkoxyphenyl substituted imidazotriazinones

ABSTRACT

The 2-phenyl-substituted imidazotriazinones having short unbranched alkyl radicals in the 9-position are prepared from the corresponding 2-phenyl-imidazotriazinones by chlorosulphonation and subsequent reaction with the amines. The compounds inhibit cGMP-metabolising phosphodiesterases and are suitable for use as active compounds in pharmaceuticals, for treating cardiovascular and cerebrovascular disorders and/or disorders of the urogenital system, in particular for treating erectile dysfunction.

The present invention relates to 2-alkoxyphenyl-substitutedimidazotriazinones, to a process for their preparation and to their useas pharmaceuticals, in particular as inhibitors of cGMP-metabolisingphosphodiesterases.

The published specification DE 28 11 780 describes imidazotriazines asbronchodilators having spasmolytic activity and inhibitory activityagainst phosphodiesterases which metabolise cyclic adenosinemonophosphate (cAMP-PDEs, nomenclature according to Beavo: PDE-III andPDE-IV). An inhibitory action against phosphodiesterases whichmetabolise cyclic guanosine monophosphate (cGMP-PDEs, nomenclatureaccording to Beavo and Reifsnyder (Trends in Pharmacol. Sci. 11,150-155, 1990): PDE-I, PDE-II and PDE-V) has not been described.Compounds having a sulphonamide group in the aryl radical in the2-position are not claimed. Furthermore, FR 22 13 058, CH 59 46 71, DE22 55 172, DE 23 64 076 and EP 000 9384 describe imidazotriazinoneswhich do not have a substituted aryl radical in the 2-position and arelikewise said to be bronchodilators having cAMP-PDE inhibitory action.

WO 94/28902 describes pyrazolopyrimidinones Which are suitable fortreating impotence.

WO 99/24433 and WO 99/67244 describe imidazotriazinones which aresuitable for treating impotence.

At this stage, 11 phosphodiesterases having varying specificity for thecyclic nucleotides cAMP and cGMP have been described in the literature(cf. Fawcett et al., Proc. Nat. Acad. Sci. 97(7), 3072-3077 (2000)).Phosphodiesterases which metabolise cyclic guanosine 3′,5′-monophosphate(cGMP-PDE's) are PDE-1, PDE-2, PDE-5, PDE-6, PDE-9, PDE-10 and PDE-11.The compounds according to the invention are potent inhibitors ofphosphodiesterase 5. Owing to the different expression of thephosphodiesterases in different cells, tissues and organs, and thedifferentiated subcellular localization of these enzymes, it ispossible, using the selective inhibitors according to the invention, toselectively increase the cGMP concentration in specific cells, tissuesand organs, thus addressing different cGMP-regulated processes. This isto be expected in particular in cases where, under certain physiologicalconditions, the synthesis of cGMP is increased. For example, duringsexual stimulation, nitrogen monoxide is released neuronally in thevessels of the Corpus cavemosum, and the synthesis of cGMP is thusincreased. This causes a considerable expansion of the vessels whichsupply the Corpus cavemosum with blood, thus resulting in an erection.Accordingly, inhibitors of cGMP-metabolising PDEs should be particularlysuitable for treating erectile dysfunction.

An increase of the cGMP concentration can lead to beneficialantiaggregatory, antithrombotic, antiprolific, antivasospastic,vasodilative, natriuretic and diuretic effects and influence conductionin the central nervous system and thus memory performance. It caninfluence the short- or long-term modulation of vascular and cardiacinotropism, of pulse and of cardiac conduction (J. C. Stoclet, T.Keravis, N. Komas and C. Lugnier, Exp. Opin. Invest. Drugs (1995), 4(11), 1081-1100).

The present invention relates to compounds of the general formula (I)

in whichR¹ represents

and to their salts and hydrates.

In the context of the invention, preference is given to physiologicallyacceptable salts. Physiologically acceptable salts can be salts of thecompounds according to the invention with inorganic or organic acids.Preference is given to salts with inorganic acids such as, for example,hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acidor salts with organic carboxylic or sulphonic acids such as, forexample, acetic acid, maleic acid, fumaric acid, malic acid, citricacid, tartaric acid, lactic acid, benzoic acid, or methanesulphonicacid, ethanesulphonic acid, phenylsulphonic acid, toluenesulphonic acidor naphthalenedisulphonic acid.

Physiologically acceptable salts can also be metal or ammonium salts ofthe compounds according to the invention. Particular preference is, forexample, given to sodium, potassium, magnesium or calcium salts, andalso to ammonium salts derived from ammonia or organic amines, such as,for example, ethylamine, di- or triethylamine, di- or triethanolamine,dicyclohexylamine, dimethylaminoethanol, arginine, lysine,ethylenediamine or 2-phenylethylamine.

The compounds according to the invention, in particular the salts, canalso be present as hydrates. In the context of the invention, hydratesare to be understood as meaning compounds which contain water in thecrystal. Such compounds can contain one or more, typically 1 to 5,equivalents of water. Hydrates can be prepared, for example, bycrystallizing the compound in question from water or a water-containingsolvent.

The compounds according to the invention can be prepared by convertingcompounds of the formula (II)

in whichL represents straight-chain or branched alkyl having up to 4 carbonatomsusing the compound of the formula (III)

in a two-step reaction in the systems ethanol and phosphorusoxytrichloride/dichloroethane into the compound of the formula (IV)

which, in a further step, is converted with chlorosulphonic acid intothe compound of the formula (V)

which is subsequently reacted with the corresponding amines in inertsolvents to give the sulphonamides or convert it into the free sulphonicacid.

The process according to the invention can be illustrated in anexemplary manner by the equation below:

Suitable solvents for the individual steps are the customary organicsolvents which do not change under the reaction conditions. Thesepreferably include ethers, such as diethyl ether, dioxane,tetrahydrofuran, glycol dimethyl ether, or hydrocarbons, such asbenzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions,or halogenated hydrocarbons, such as dichloromethane, trichloromethane,carbon tetrachloride, dichloroethane, trichloroethylene orchlorobenzene, or ethyl acetate, dimethylformamide, hexamethylphosphorictriamide, acetonitrile, acetone, dimethoxyethane or pyridine. It is alsopossible to use mixtures of the solvents mentioned. Particularlypreferably, ethanol is used for the first step and dichloroethane forthe second step.

The reaction temperature can generally be varied within a relativelywide range. In general, the reaction is carried out in a range of from−20° C. to 200° C., preferably from 0° C. to 70° C.

The process steps according to the invention are generally carried outat atmospheric pressure. However, it is also possible to operate underelevated or reduced pressure (for example in the range of from 0.5 to 5bar).

The conversion into the compounds of the formula (V) is carried out in atemperature range of from 0° C. to room temperature and at atmosphericpressure.

The reaction with the corresponding amines is carried out in one of theabovementioned chlorinated hydrocarbons, preferably in dichloromethane.

The reaction temperature can generally be varied within a relativelywide range. In general, the reaction is carried out in a range of from−20° C. to 200° C., preferably from 0° C. to room temperature.

The reaction is generally carried out at atmospheric pressure. However,it is also possible to operate under elevated or reduced pressure (forexample in the range of from 0.5 to 5 bar).

The compounds of the formula (II) can be prepared by convertingcompounds of the general formula (VII)CH₃CH₂CH₂—CO-T  (VII)in whichT represents halogen, preferably chlorine,initially by reaction with D, L-alanine of the formula (VIII)

in inert solvents, if appropriate in the presence of a base andtrimethylsilyl chloride, into the compound of the formula (IX)

followed by reaction with the compound of the formula (X)

in whichL is as defined abovein inert solvents, if appropriate in the presence of a base.

Suitable solvents for the individual steps of the process are thecustomary organic solvents which do not change under the reactionconditions. These preferably include ethers, such as diethyl ether,dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons, suchas benzene, toluene, xylene, hexane, cylohexane or mineral oilfractions, or halogenated hydrocarbons, such as dichloromethane,trichloromethane, carbon tetrachloride, dichloroethylene,trichloroethylene or chlorobenzene, or ethyl acetate, dimethylformamide,hexamethylphosphoric triamide, acetonitrile, acetone, dimethoxyethane orpyridine. It is also possible to use mixtures of the solvents mentioned.Particularly preferably, dichloromethane is used for the first step anda mixture of tetrahydrofuran and pyridine for the second step.

Suitable bases are, in general, alkali metal hydrides or alkoxides, suchas, for example, sodium hydride or potassium tert-butoxide, or cyclicamines, such as, for example, piperidine, pyridine,dimethylaminopyridine, or C₁-C₄-alkylamines, such as, for example,triethylamine. Preference is given to triethylamine, pyridine and/ordimethylaminopyridine.

The base is generally employed in an amount of from 1 mol to 4 mol,preferably from 1.2 mol to 3 mol, in each case based on 1 mol of thecompound of the formula (X).

The reaction temperature can generally be varied in a relatively widerange. In general, the reaction is carried out in a range of from −20°C. to 20° C., preferably from 0° C. to 100° C.

The compounds of the formulae (VII), (VIII) and (X) are known per se.

The compound of the formula (III) can be prepared by reacting thecompound of the formula (XI)

with ammonium chloride in toluene and in the presence oftrimethylaluminium in hexane in a temperature range of from −20° C. toroom temperature, preferably at 0° C., and at atmospheric pressure andreacting the resulting amidine, if appropriate in situ, with hydrazinehydrate.

The compound of the formula (XI) is known per se.

The compounds according to the invention have an unforeseeable usefulpharmacological activity spectrum.

They inhibit cGMP-metabolising phosphodiesterase 5. This results in anincrease of cGMP. Owing to the differentiated expression of thephosphodiesterases in different cells, tissues and organs and thedifferentiated subcellular localization of these enzymes, it ispossible, using the selective inhibitors according to the invention, toselectively address the various cGMP-regulated processes.

Moreover, the compounds according to the invention enhance the activityof substances such as, for example, EDRF (endothelium-derived relaxingfactor), ANP (atrial natriuretic peptide), of nitrovasodilators and allother substances which increase the cGMP concentration in a mannerdifferent from that of phosphodiesterase inhibitors.

The compounds of the general formula (I) according to the invention aretherefore suitable for the prophylaxis and/or treatment of disorderswhere an increase of the cGMP concentration is beneficial, i.e.disorders which are associated with cGMP-regulated processes (in mostcases simply referred to as “cGMP-related diseases”). These includecardiovascular disorders, disorders of the urogenital system and alsocerebrovascular disorders.

For the purpose of the present invention, the term “cardiovasculardisorders” includes disorders such as, for example, hypertension,pulmonary hypertension, stable and unstable angina, peripheral andcardial vasculopathies, arrhythmia, thromboembolic disorders andischemias such as myocardial infarction, stroke, transitory and ischemicattacks, angina pectoris, obstruction of peripheral circulation,prevention of restinoses after thrombolysis therapy, percutaneoustransluminal angioplasty (PTA), percutaneous transluminal coronaryangioplasties (PTCA) and bypass.

Furthermore, the compounds of the general formula (I) according to theinvention may also be of significance for cerebrovascular disorders.These include, for example, cerebral ischemia, stroke, reperfusiondamage, brain trauma, oedema, cerebral thrombosis, dementia, reducedmemory performance and Alzheimer's disease.

Owing to their relaxing action on smooth muscles, they are suitable fortreating motility disturbances in the digestive tract such asgastroparesis and disorders of the urogenital system such as hypertrophyof the prostate, BHP, incontinence and in particular for treatingerectile dysfunction and female sexual dysfunction.

Activity of the phosphodiesterases (PDEs)

To test the inhibiting action, the “Phosphodiesterase [³H] cGMP-SPAenzyme assay” from Amersham Life Science was used. The test was carriedout according to the manufacturer's test protocol. Use was made of humanrecombinant PDE5 which was expressed in a bacculovirus system. Thesubstance concentration at which the reaction rate is reduced by 50% wasmeasured.

Inhibition of the Phosphodiesterases In Vitro

TABLE 1 PDE V Ex. No. IC₅₀ [nM] 1 4.2 2 19 3 19 4 2.4

In principle, inhibition of phosphodiesterase 5 results in an increaseof the cGMP concentration. Thus, the compounds are of interest for alltherapies in which an increase of the cGMP concentration is consideredto be beneficial.

The erection-stimulating action was investigated using rabbits whichwere awake [Naganuma H, Egashira T, Fuji J, Clinical and ExperimentalPharmacology and Physiology 20, 177-183 (1993)]. The substances wereadministered intravenously, orally or parenterally.

The novel active compounds and their physiologically acceptable salts(for example hydrochlorides, maleates or lactates) can be converted in aknown manner into the customary formulations, such as tablets, coatedtablets, pills, granules, aerosols, syrups, emulsions, suspensions andsolutions, using inert non-toxic, pharmaceutically suitable excipientsor solvents. In this case the therapeutically active compound should ineach case be present in a concentration from approximately 0.5 to 90% byweight of the total mixture, i.e. in amounts which are sufficient toachieve the dosage range indicated.

The formulations are prepared, for example, by extending the activecompounds using solvents and/or excipients, if appropriate usingemulsifiers and/or dispersants, it optionally being possible, forexample, to use organic solvents as auxiliary solvents if the diluentused is water.

Administration is carried out in a customary manner, preferably orally,transdermally or parenterally, for example perlingually, buccally,intravenously, nasally, rectally or inhalatively.

For human use, in the case of oral administration, it is good practiceto administer doses of from 0.001 to 50 mg/kg, preferably of 0.01mg/kg-20 mg/kg. In the case of parenteral administration, such as, forexample, via mucous membranes nasally, buccally or inhalatively, it isgood practice to use doses of 0.001 mg/kg-0.5 mg/kg.

In spite of this, if appropriate it may be necessary to depart from theamounts mentioned, namely depending on the body weight or the type ofadministration route, on the individual response towards the medicament,the manner of its formulation and the time or interval at whichadministration takes place. Thus, in some cases it may be adequate tomanage with less than the abovementioned minimum amounts, while in othercases the upper limit mentioned has to be exceeded. In the case of theadministration of relatively large amounts, it may be advisable todivide these into several individual doses over the course of the day.

The compounds according to the invention are also suitable for use inveterinary medicine. For use in veterinary medicine, the compounds ortheir non-toxic salts can be administered in a suitable formulation inaccordance with general veterinary practice. Depending on the kind ofanimal to be treated, the veterinary surgeon can determine the nature ofuse and the dosage.

Starting Materials

EXAMPLE 1A 2-Butyrylaminopropionic acid

22.27 g (250 mmol) of D, L-alanine and 55.66 g (550 mmol) oftriethylamine are dissolved in 250 ml of dichloromethane, and thesolution is cooled to 0° C. 59.75 g (550 mmol) of trimethylsilylchloride are added dropwise, and the solution is stirred at roomtemperature for 1 hour and at 40° C. for one hour. After cooling to −10°C., 26.64 g (250 mmol) of butyryl chloride are added dropwise, and theresulting mixture is stirred at −10° C. for 2 hours and at roomtemperature for one hour.

With ice-cooling, 125 ml of water are added dropwise and the reactionmixture is stirred at room temperature for 15 minutes. The aqueous phaseis evaporated to dryness, the residue is triturated with acetone and themother liquor is filtered off with suction. The solvent is removed, andthe residue is then chromatographed. The resulting product is dissolvedin 3N aqueous sodium hydroxide solution and the resulting solution isevaporated to dryness. The residue is taken up in conc. HCl and againevaporated to dryness. The residue is stirred with acetone, theprecipitated solid is filtered off and the solvent is removed underreduced pressure. This gives 28.2 g (71%) of a viscous oil whichcrystallizes after a while.

200 MHz ¹H-NMR (DMSO-d₆): 0.84, t, 3H, 1.22, d, 3H, 1.50 hex, 2H, 2.07,t, 2H; 4.20, quin., 1H, 8.09, d, 1H.

EXAMPLE 2A 2-Ethoxybenzonitrile

25 g (210 mmol) of 2-hydroxybenzonitrile, 87 g of potassium carbonateand 34.3 g (314.8 mmol) of ethyl bromide in 500 ml of acetone arerefluxed overnight. The solid is filtered off, the solvent is removedunder reduced pressure and the residue is distilled under reducedpressure. This gives 30.0 g (97%) of a colourless liquid.

200 MHz ¹H-NMR (DMSO-d₆): 1.48, t, 3H, 4.15, quart., 2H, 6.99, dt, 2H,7.51, dt, 2H.

EXAMPLE 3A 2-Ethoxybenzamidine hydrochloride

21.4 g (400 mmol) of ammonium chloride are suspended in 375 ml oftoluene, and the suspension is cooled to 0° C. 200 ml of a 2M solutionof trimethylaluminium in hexane are added dropwise, and the mixture isstirred at room temperature until the evolution of gas has ceased. 29.44g (200 mmol) of 2-ethoxybenzonitrile are added, and the reaction mixtureis then stirred at 80° C. (bath) overnight.

With ice-cooling, the cooled reaction mixture is added to a suspensionof 100 g of silica gel and 950 ml of chloroform, and the mixture isstirred at room temperature for 30 minutes. The mixture is filtered offwith suction and the residue is washed with the same amount of methanol.The mother liquor is concentrated and the resulting residue is stirredin a mixture of dichloromethane and methanol (9:1), the solid isfiltered off with suction and the mother liquor is concentrated. Thisgives 30.4 g (76%) of a colourless solid.

200 MHz ¹H-NMR (DMSO-d₆): 1.36; t, 3H, 4.12, quart., 2H, 7.10, t, 1H,7.21, d, 1H, 7.52, m, 2H, 9.30, s, broad, 4H.

EXAMPLE 4A2-(2-Ethoxyphenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f]-1,2,4-triazin-4-one

7.16 g (45 mmol) of 2-butyrylaminopropionic acid and 10.67 g of pyridineare dissolved in 45 ml of THF and, after addition of a spatula tip ofDMAP, heated at reflux. 12.29 g (90 mmol) of ethyl oxalyl chloride areslowly added dropwise, and the reaction mixture is refluxed for 3 hours.The mixture is poured into ice-water and extracted three times withethyl acetate, and the extracts are dried over sodium sulphate andconcentrated. The residue is taken up in 15 ml of ethanol and refluxedwith 2.15 g of sodium bicarbonate for 2.5 hours. The cooled solution isfiltered.

With ice-cooling, 2.25 g (45 mmol) of hydrazine hydride are addeddropwise to a solution of 9.03 g (45 mmol) of 2-ethoxybenzamidinehydrochloride in 45 ml of ethanol, and the resulting suspension isstirred at room temperature for 10 minutes. The ethanolic solutiondescribed above is added to this reaction mixture, and the mixture isstirred at a bath temperature of 70° C. for 4 hours. Followingfiltration, the solution is concentrated, the residue is partitionedbetween dichloromethane and water, the organic phase is dried oversodium sulphate and the solvent is removed under reduced pressure.

This residue is dissolved in 60 ml of 1,2-dichloroethane and, afteraddition of 7.5 ml of phosphorus oxychloride, refluxed for 2 hours. Themixture is diluted with dichloromethane and neutralized by addition ofsodium bicarbonate solution and solid sodium bicarbonate. The organicphase is dried and the solvent is removed under reduced pressure.Chromatography with ethyl acetate and crystallization gives 4.00 g (28%)of a colourless solid, R_(f)=0.42 (dichloromethane/methanol=95:5).

200 MHz ¹H-NMR (CDCl₃): 1.02, t, 3H, 1.56, t, 3H, 1.89, hex, 2H, 2.67,s, 3H, 3.00, t, 2H, 4.26, quart., 2H, 7.05, m, 2H, 7.50, dt, 1H; 8.17,dd, 1H, 10.00, s, 1H.

EXAMPLE 5A4-Ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f]-1,2,4-triazin-2-yl)benzenesulphonyl chloride

At 0° C., 2.00 g (6.4 mmol) of2-(2-ethoxyphenyl)-5-methyl-7-propyl-3H-imidazo-[5,1-f]-1,2,4-triazin-4-oneare added slowly to 3.83 ml of chlorosulphonic acid. The reactionmixture is stirred at room temperature overnight, poured into ice-waterand extracted with dichloromethane. This gives 2.40 g (91%) of acolourless foam.

200 MHz ¹H-NMR (CDCl₃): 1.03, t, 3H, 1.61, t, 2H, 1.92, hex, 2H, 2.67,s, 3H, 3.10, t, 2H, 4.42, quart, 2H, 7.27, t, 1H; 8.20, dd, 1H; 8.67, d,1H, 10.18 s, 1H.

PREPARATION EXAMPLES Example 12-[2-Ethoxy-5-(1-piperazinylsulphonyl)phenyl]-5-methyl-7-propylimidazo-[5,1-f]-1,2,4-triazin-4(3H)-one

2.2 g (5.354 mmol) of the sulphonyl chloride from Example 5A aredissolved in 10 ml of dichloromethane and added dropwise to a solutionof 4.61 g (53.54 mmol) of piperazine in 20 ml of dichloromethane. Themixture is stirred at RT for 10 min and the organic phase is washed withwater, dried over sodium sulphate and concentrated. The product isrecrystallized from ethyl acetate.

Yield: 1.83 g (74.2%)

M.p.: 256° C.

¹H-NMR (CD₃OD): δ=1.0 (t, 3H); 1.45 (t, 3H); 1.72 (sextett, 2H); 2.6 (s,3H); 2.85-2.9 (m, 4H); 2.9-3.0 (m, 6H); 4.3 (q, 2H); 7.4 (d, 1H); 7.9(dd, 1H); 8.0 (d, 1H).

Example 22-{2-Ethoxy-5-[(4-ethyl-4-hydroxy-4λ⁵-piperazin-1-yl)sulphonyl]phenyl}-5-methyl-7-propylimidazo[5,1-f]-1,2,4-triazin-4(3H)-one

The preparation is carried out analogously to Example 1 using 0.69 g(1.67 mmol) of the sulphonyl chloride from Example 5A and 0.57 g (5mmol) of ethylpiperazine. 0.5 g (1.023 mmol) of the resultingsulphonamide and 0.176 g (1.023 mmol) of 3-chloroperoxybenzoic acid arestirred in 5 ml of dichloromethane at RT for 1 h. The mixture isextracted 3× with saturated sodium carbonate solution, dried over sodiumsulphate and concentrated. The residue is purified by chromatography onsilica gel (mobile phase: dichloromethane/methanol 10: 1).

Yield: 0.13 g (25.2%)

M.p.: 224-225° C.

¹H-NMR (CD₃OD): δ=0.95 (t, 3H); 1.3 (t, 3H); 1.45 (t, 3H); 1.7 (sextett,2H); 2.6 (s, 3H); 2.9-3.0 (m, 4H); 3.1-3.2 (m, 4H); 3.4-3.5 (m, 2H); 3.7(d, 2H); 4.3 (q, 2H); 7.35 (d, 1H); 7.75 (dd, 1H); 8.05 (d, 1H)

Example 34-Ethoxy-N-[2-(ethylamino)ethyl]-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f]-1,2,4-triazin-2-yl)benzenesulphonamide

The preparation was carried out analogously to Example 1 using 2.2 g(5.35 mmol) of the sulphonyl chloride from Example 5A and 4.72 g (53.5mmol) of ethylethylenediamine.

Yield: 1.4 g (56.5%)

M.p.: 148-150° C.

¹H-NMR (CD₃OD): δ=0.95 (t, 3H); 1.1 (t, 3H); 1.45 (t, 3H); 1.7 (sextett,2H); 2.6 (s, 3H); 2.62 (q, 2H); 2.7 (t, 2H); 2.95 (t, 2H); 3.0 (t, 2H);4.25 (q, 2H); 7.3 (d, 1H); 8.0 (dd, 1H); 8.1 (d, 1H)

Example 4N-(2-aminoethyl)-4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f]-1,2,4-triazin-2-yl)benzenesulphonamide

1.0 g (2.434 mmol) of the sulphonyl chloride from Example 5A and 0.34 g(2.677 mmol) of glycine methyl ester hydrochloride, together with 0.57 g(5.598 mmol) of triethylamine, are stirred in 10 ml of dichloromethaneat RT for 30 min. The mixture is extracted with dilute hydrochloric acidsolution and then with saturated sodium chloride solution, and theorganic phase is dried using sodium sulphate. The solvent is evaporatedand the residue (0.96 g) is taken up in 20 ml of methanol and, afteraddition of 4.1 ml of 1 molar sodium hydroxide solution, stirred at RTfor 3 h. The methanol is evaporated and the residue is treated with 10ml of dilute HCl solution and extracted 2× with ethyl acetate. Theorganic phase is dried with sodium sulphate and then carefullyconcentrated, whereupon the product crystallizes out.

Yield: 0.307 g (33.3%)

¹H-NMR (DMSO): δ=0.9 (t, 3H); 1.3 (t, 3H); 1.7 (sextett, 2H); 2.45 (s,3H); 2.85 (t, 2H); 3.6 (d, 2H); 4.2 (q, 2H); 7.35 (d, 1H); 7.85-7.95 (m,2H); 8.1 (t, 1H)

Example 6{[2-({[4-Ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f]-1,2,4-triazin-2-yl)phenyl]sulphonyl}amino)ethyl]amino}(oxo)aceticacid

0.34 g (0.782 mmol) of the amine from Example 4 and 0.13 g (0.939 mmol)of ethyl oxalyl chloride, together with 0.2 g (1.956 mmol) oftriethylamine, are stirred in 15 ml of dichloromethane at RT for 30 min.The mixture is concentrated and the residue is purified on silica gel(mobile phase: dichloromethane/methanol 50:1). This gives 0.18 g (43%)of the ethyl ester which is taken up in 5 ml of methanol. Followingaddition of 0.03 g (0.673 mmol) of sodium hydroxide in 2 ml of water,the mixture is stirred at RT for 30 min. The methanol is evaporated andthe residue is treated with 5 ml of dilute HCl solution and extracted 2×with ethyl acetate. After drying over sodium sulphate, the solution isconcentrated.

Yield: 0.023 g (13.5%)

¹H-NMR (CDCl₃/CD₃OD): δ=1.05 (t, 3H); 1.55 (t, 3H); 1.9 (sextett, 2H);2.25 (s, 3H); 3.1-3.2 (m, 4H); 3.3-3.45 (m, 2H); 4.25-4.4 (q, 2H); 7.15(d, 1H); 8.0 (dd, 1H); 8.3 (d, 1H)

Example 72-{2-Ethoxy-5-[(3-oxo-1-piperazinyl)sulphonyl]phenyl}-5-methyl-7-propylimidazo[5,1-f]-1,2,4-triazin-4(3H)-one

The preparation was carried out analogously to Example 1 using 0.66 g(1.606 mmol) of the sulphonyl chloride from Example 5A and 0.4 g (4.016mmol) of 2-piperazinone.

The preparation was carried out analogously to Example 1 using 2.2 g(5.35 mmol) of the sulphonyl chloride from Example 5A and 3.22 g (53.5mmol) of ethylenediamine.

Yield: 1.13 g (48.6%)

M.p.: 226-228° C.

¹H-NMR (CD₃OD): δ=1.0 (t, 3H); 1.45 (t, 3H); 1.72 (sextett, 2H); 2.6 (s,3H); 2.7 (t, 2H); 2.9-3.0 (m, 4H); 4.25 (q, 2H); 7.35 (d, 1H); 8.0 (dd,1H); 8.1 (d, 1H)

Example 5N-{[4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f]-1,2,4-triazin-2-yl)phenyl]sulphonyl}-glycine

Yield: 0.613 g (80.4%)

¹H-NMR (CD₃OD): δ=1.0 (t, 3H); 1.45 (t, 3H); 1.8 (sextett, 2H); 2.6 (s,3H); 2.95 (t, 2H); 3.3-3.4 (m, 4H); 3.7 (s, 2H); 4.3 (q, 2H); 7.4 (d,1H); 8.0 (dd, 1H); 8.1 (d, 1H)

Example 84-Ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f]-1,2,4-triazin-2-yl)benzenesulphonicacid

0.33 g (0.803 mmol) of the sulphonyl chloride from Example 5A are mixedwith 10 ml of water and 5 ml of acetonitrile and stirred at roomtemperature for 18 hours. The resulting solution is then concentratedand the residue is dissolved in 60 ml of acetonitrile and filtered. Thefiltrate is concentrated again.

Yield: 0.28 g (88.7%)

¹H-NMR (CD₃OD): δ=0.95 (t, 3H); 1.45 (t; 3H); 1.7 (sextett; 2H); 2.6 (s,3H); 2.7 (t, 2H); 4.25 (q, 2H); 7.35 (d, 1H); 8.0 (dd, 1H); 8.1 (d, 1H)

Example 94-Ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f]-1,2,4-triazin-2-yl)benzenesulphonamide

0.33 g (0.803 mmol) of the sulphonyl chloride from Example 5A aretreated with 5 ml of 25% strength ammonia solution and stirred at roomtemperature for 2 hours. The solvent is then removed under reducedpressure. The residue is suspended in 10 ml of ice-water, filtered off,washed twice with in each case 10 ml of ice-water and dried in a vacuumdesiccator.

Yield: 0.266 g (85.0%).

¹H-NMR (CD₃OD): δ=1.0 (t, 3H); 1.45 (t; 3H) 1.75 (sextett; 2H); 2.6 (s,3H); 2.7 (t, 2H); 4.25 (q, 2H); 7.3 (d, 1H); 8.0 (dd, 1H); 8.1 (d, 1H)

1. Compounds of the general formula (I)

in which R¹ represents

and their salts and hydrates.
 2. (canceled)
 3. Process for preparingcompounds according to claim 1, characterized in that compounds of theformula (II)

in which L represents straight-chain or branched alkyl having up to 4carbon atoms are converted using the compound of the formula (III)

in a two-step reaction in the systems ethanol and phosphorusoxytrichloride/dichloroethane into the compound of the formula (IV)

which, in a further step, is converted with chlorosulphonic acid intothe compound of the formula (V)

which is subsequently reacted with the corresponding amines in inertsolvents to give the sulphonamides or converted into the free sulphonicacid.
 4. A pharmaceutical composition comprising at least one compoundaccording to claim 1 and pharmaceutically acceptable formulating agents.5. A method for treating cardiovascular and cerebrovascular disordersand/or disorders of the urogenital tract comprising administering to asubject in need thereof an effective amount of a compound of claim
 1. 6.The method of claim 5 wherein the disorder of the urogenital tract iserectile dysfunction.
 7. (canceled)
 8. (canceled)